The exclusively human bacterial pathogens N. meningitidis and N. gonorrhoeae are capable of colonizing and penetrating the human mucosa, to avoid host's defenses and to persist in various anatomical niches. In clinical terms, these events may translate in a variety of syndromes ranging from non-symptomatic carriage, to life-threatening bacterial meningitis or pelvic inflammatory disease with tubule scarring. Our aim is to determine the molecular machineries that drive the bacterial survival in the human host and that cause the infection-associated pathology with the ultimate goal to give direction to the development of new therapeutic strategies and vaccines. This project covers a key aspect of neisserial pathogenesis and aims to identify bacterial and host cell determinants that are critical to the establishment of an infection and may be direct targets of infection intervention. The work follows a combined genetic, cell biological and biochemical approach including the genetic manipulation of putative bacterial pathogenicity factors, and the isolation and biochemical purification of relevant bacterial surface antigens and host cell molecules (receptors). In the last year, this investment has led to (a) discovery of receptors (i.e., epithelial cell heparan sulfate proteoglycans) utilized by the Opc adhesin of N. meningitidis to invade human cells, (b) evidence that meningococcal capsule and LPS sialylation modulate the function of Opc as a bacterial adhesin, (c) recognition that gonococcal Opa adhesins facilitate uptake of the pathogen by human professional phagocytes and that this event is accompanied by a phagocytic respiratory burst, and (d) evidence that neisserial pili stimulate non-opsonophagocytosis of the pathogen by monocytes, an event which is not accompanied by an oxidative response. These findings provide important insights in the function of the variation in bacterial surface antigens that typifies the pathogenic Neisseria species, and suggest that this variation does not only serve as an immune escape mechanism but serves as a bacterial adaptation strategy to survive at various niches encountered in the host. This perception is of particular interest from the perspective of vaccine development as it implies that the course of infection may be modulated by targeting distinct variable surface antigens.